1. Technical Field
This invention relates generally to novel compounds and methods for effectuating change in human hypothalamic function, thereby altering certain behavior and physiology mediated by the hypothalamus of individuals. More particularly, the invention relates to the use of certain Estrene steroids as neurochemical effectuators of physiology and behavior.
2. Description of the Related Art
The present invention relates to certain compounds, namely Estrene steroids and related compounds as will be described herein, and methods of using these compounds as human semiochemicals in order to alter hypothalamic function, thereby affecting certain consequent behavior and physiology, e.g. the reduction of anxiety. Estrene steroids are typified by 17xcex2-Estradiol (1,3,5(10)-Estratriene-3,17xcex2-diol), and are characterized by a phenolic 1,3,5(10) A-ring and a hydroxy or hydroxy derivative, such as an ether or ester, at the 3-position. The pheromone properties of some Estrene steroids for some mammalian species has been described. Michael, R. P. et al., Nature (1968) 218:746 refers to Estrogens (particularly Estradiol) as a pheromonal attractant of male rhesus monkeys. Parrot, R. F., Hormones and Behavior (1976) 7:207-215, reports Estradiol benzoate injection induces mating behavior in ovariectomized rats; and the role of the blood level of Estradiol in make sexual response (Phoenix, C. H., Physiol. and Behavior (1976) 16:305-310) and female sexual response (Phoenix, C. H., Hormones and Behavior (1977) 8:356-362) in Rhesus monkeys has been described. On the other hand, there is little agreement in the literature as to whether or not pheromones as such play any role in the reproductive behavior and interpersonal communication of mammals (Beauchamp, G. K., et al., xe2x80x9cThe Pheromone Concept in Mammalian Chemical Communication: A Critiquexe2x80x9d, In: Mammalian Olfaction, Reproductive Processes, and Behavior, Doty, R. L., Ed., Academic Press, 1976).
An embodiment of the subject invention concerns the non-systemic, nasal administration of certain Estrene steroids to affect a specific behavioral or physiological response in human subjects, e.g. a reduction of negative affect, mood, and character traits. In particular, nasal administration provides for contacting neuroreceptors of a heretofore poorly understood neuroendocrine structure, commonly known as the vomeronasal organ (xe2x80x9cVNOxe2x80x9d; also known as xe2x80x9cJacobson""s organxe2x80x9d), with one or more steroid(s) or with compositions containing the steroid(s). This organ is accessed through the nostrils of most higher animalsxe2x80x94from snakes to humans, and has been associated, inter alia, with pheromone reception in certain species (see generally Muller-Schwarze and Silverstein, Chemical Signals, Plenum Press, New York (1980)). The axons of the neuroepithelia of the vomeronasal organ, located supra palatial, form the vomeronasal nerve and have direct synaptic connection to the accessory olfactory bulb and indirect input from there to the cortico-medial amygdaloid forebrain and hypothalamic nuclei of the brain. The distal axons of the terminal is nerve neurons may also serve as neurochemical receptors in the VNO. Stensaas, L. J., et al., J. Steroid Biochem. and Molec. Biol. (1991) 39:553. This nerve has direct synaptic connection with the hypothalamus.
Johnson, A. et al. (J. Otolaryngology (1985) 14:71-79) report evidence for the presence of the vomeronasal organ in most adult humans, but conclude that the organ is probably non-functional. Contravening results which suggest that the VNO is a functional chemosensory receptor are reported by Stensaas, L., et al., supra; and by Moran, D. T., et al., Garcia-Velasco, J. and M. Mondragoni Monti-Bloch, L. and B. Grosserxe2x80x94all in J. Steroid Biochem. and Molec. Biol. (1991) 39.
It is apparent that it would be desirable to identify and synthesize human semiochemicals and pheromones and to develop pharmaceutical compositions and methods of use to influence hypothalamic function. This invention relates to the unexpected discovery that, when nasally administered to human subjects, certain neurochemical ligands, particularly certain Estrene steroids and related compounds, or pharmaceutical compositions containing certain Estrenes or related compounds, specifically bind to chemoreceptors of nasal neuroepithelial cells and this binding generates a series of neurolophysiological responses resulting in an alteration of hypothalamic function of an individual. When properly administered, the effect of certain of these compounds on the hypothalamus affects the function of the autonomic nervous system and a variety of behavioral or physiological phenomena which include, but are not limited to the following: anxiety, premenstrual stress, fear, aggression, hunger, blood pressure, and other behavioral and physiological functions normally regulated by the hypothalamus. Otto Appenzeller. The Autonomic Nervous System. An introduction of basic and clinical concepts (1990); Korner, P. I. Central nervous control of autonomic cardiovascular function, and Levy, N. M. and Martin, P. J. Neural control of the heart, both in Handbook of Physiology; Section 2: Cardiovascular Systemxe2x80x94the heart, Vol I, Washington D.C., 1979, American Physiological Society; Fishman, A. P., et al. editors, Handbook of Physiology. Section 3: Respiratory System. Vol. II. Control of breathing. Bethesda Md. 1986. American Physiological Society.
In some instances a single Estrene steroid, or related compound, is administered, in some instances combinations of Estrene steroids and/or related compounds are administered.
Accordingly, it is an object of this invention to provide novel steroids which are human semiochemicals or pheromones and are suitable for nasal administration in an individual.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
Objects of this invention are achieved by steroids with the formula: 
wherein R1 is selected from the group consisting essentially of one or two hydrogen atoms, methyl, methylene, and one or two halo atoms; R2 is absent or is selected from the group consisting essentially of hydrogen and methyl; R3 is selected from the group consisting essentially of oxo, hydroxy, lower alkoxy, lower acyloxy, benzoyl, cypionyl, glucuronide and sulfonyl; R4 is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy, lower acyloxy, oxo and halo; R5 is absent or is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy and lower acyloxy; R6 is a hydrogen or a halo; and xe2x80x9caxe2x80x9d represents optional aromatic unsaturation of ring A of said steroid, or xe2x80x9cbxe2x80x9d, xe2x80x9ccxe2x80x9d, and xe2x80x9cdxe2x80x9d are each optional double bonds; and xe2x80x9cexe2x80x9d, xe2x80x9cfxe2x80x9d, xe2x80x9cgxe2x80x9d, xe2x80x9chxe2x80x9d, xe2x80x9cixe2x80x9d and xe2x80x9cjxe2x80x9d are each optional double bonds. In this embodiment, the steroid is preferrably administered in the form of a pharmaceutical composition containing one or more pharmaceutically acceptable carriers; with the provisos that:
(I) when xe2x80x9caxe2x80x9d is present, R3 is hydroxy, and xe2x80x9cjxe2x80x9d, xe2x80x9cixe2x80x9d, xe2x80x9cgxe2x80x9d and xe2x80x9chxe2x80x9d are all absent, then (a) R4 cannot be hydrogen; or (b) R4 cannot be oxo if xe2x80x9cexe2x80x9d and xe2x80x9cfxe2x80x9d are absent;
(II) when xe2x80x9caxe2x80x9d is present, R3 is hydroxy; and xe2x80x9cjxe2x80x9d, xe2x80x9cixe2x80x9d and xe2x80x9cgxe2x80x9d are all absent, xe2x80x9chxe2x80x9d is present, then R1 cannot be methylene;
(III) when xe2x80x9caxe2x80x9d, xe2x80x9chxe2x80x9d and xe2x80x9cixe2x80x9d are present, (a) then at least one of xe2x80x9cexe2x80x9d or xe2x80x9cfxe2x80x9d is present, (b) R1 is methylene, or (c) R1 is not hydrogen.
(IV) when xe2x80x9cbxe2x80x9d is present, R3 is oxo, xe2x80x9cgxe2x80x9d, xe2x80x9chxe2x80x9d, xe2x80x9cixe2x80x9d, xe2x80x9cjxe2x80x9d are all absent, R5 is hydrogen, (a) then R1 cannot be one or two hydrogens if xe2x80x9cfxe2x80x9d is absent, or (b) if xe2x80x9cfxe2x80x9d is present R1 cannot be methyl;
(V) when xe2x80x9cbxe2x80x9d and xe2x80x9cjxe2x80x9d are present and R3 is oxo, hen at least one of xe2x80x9cexe2x80x9d or xe2x80x9cfxe2x80x9d must be present or R1 must be methylene;
(VI) when xe2x80x9ccxe2x80x9d is present, xe2x80x9cdxe2x80x9d is absent and R3 is hydroxy, then (a) at least xe2x80x9cexe2x80x9d or xe2x80x9cfxe2x80x9d must be present, or (b) R1 must be methylene;
(VII) when xe2x80x9ccxe2x80x9d and xe2x80x9cdxe2x80x9d are present and R3 is methoxy, then (a) at least xe2x80x9cexe2x80x9d or xe2x80x9cfxe2x80x9d must be present or (b) R1 must be methylene;
(VIII) when xe2x80x9cbxe2x80x9d is present, R3 is hydroxy and R5 is hydrogen, then (a) at least xe2x80x9cexe2x80x9d or xe2x80x9cfxe2x80x9d must be present or (b) R1 must be methylene.
A preferred class of compounds are those in which xe2x80x9caxe2x80x9d is present and xe2x80x9cgxe2x80x9d, xe2x80x9chxe2x80x9d or xe2x80x9cixe2x80x9d are optional double bonds. Another preferred class contains xe2x80x9cbxe2x80x9d, xe2x80x9ccxe2x80x9d or xe2x80x9cjxe2x80x9d as a double bond. Yet another class contains xe2x80x9ccxe2x80x9d and xe2x80x9cdxe2x80x9d as double bonds. Still another class contains R2 as methyl and xe2x80x9cexe2x80x9d as a double bond.
The term lower alkyl, lower alkoxy, etc., encompasses carbon chains of 1 to 6 carbon atoms, preferrably 1 to 4 carbon atoms. Halo includes I, Br, F and Cl.
The steroids of the invention alter hypothalamic function and autonomic function in an individual. A ligand for a chemoreceptor displayed on the surface of a nasal neuroepithelial cell is provided wherein the cell is a part of tissue other than olfactory epithelia; and, the ligand is administered within a nasal passage of the individual such that the ligand binds specifically to the chemoreceptor, resulting in an alteration of hypothalamic function of the individual.
All embodiments of this application relate to and include the functional equivalents of the steroid structures disclosed in these embodiments and to those modified steroids which demonstrate said functional equivalence, whether or not the modified steroids are explicitly disclosed.